Noroviruses are the most important cause of food-borne gastroenteritis worldwide and cause ~85-96% of selected outbreaks of acute non-bacterial gastroenteritis in the US. Heralded as the stomach flu, retirement community outbreaks are pervasive and can result in 1-2% mortality rates in the elderly. Based on capsid sequences norovirus are divided into 5 genogroups. Genogroup I (GI) and II (GII) account for almost all human infections. Each genogroup is further divided into genotypes. The GII.4 genotype is the causative agent of 70-80% of all norovirus outbreaks worldwide. The norovirus major capsid protein forms an icosohedral shell, contains major antigenic determinants and interacts with histoblood group antigen (HBGA) carbohydrates, putative receptors for entry. This study investigates the molecular mechanisms governing norovirus capsid evolution, structure and HBGA recognition as a function of immune driven antigenic drift and deceptive imprinting. We identify the mechanisms by which replacement strains evolve over time, recognize new HBGA carbohydrate binding targets, and escape from highly penetrent host susceptibility alleles and protective herd immunity. While defining the relationships between mutation, antigenic variation, immunogenicity, deceptive imprinting, structure and HGBA binding, our interdisciplinary team simultaneously develops a robust GII.4 challenge model in swine and characterizes human monoclonal antibodies (mAb) to GI and GII strains, providing key reagents for advancing the field. PUBLIC HEALTH RELEVANCE: for Noro grant Noroviruses are the most important cause of food-borne gastroenteritis worldwide and cause ~85-96% of selected outbreaks of acute non-bacterial gastroenteritis in the US. Noroviruses are transmitted via ingestion of fecally contaminated food and water, exposure to contaminated surfaces, aerosolized vomitus and direct person-to-person contact. The tremendous public health significance of norovirus is evidenced by the estimated ~23,000,000 infections, 50,000 hospitalizations, and 310 fatal cases in the US. In developing nations, repeat infection likely contribute to malnutrition in infants and young children and may result in death. This proposal tests the hypothesis that Norovirus strains evolve over time to use varying cellular receptors and avoid host immune surveillance. If this model is correct, then long-term strain specific protective immunity and immune prophylaxis can be formulated to protect against contemporary strain infections providing a much needed vaccination strategy against this important human pathogen.